Cat Blood, Dog Liver and a Dose of Luck

Jay McLean walked into Dr. William Howell’s laboratory at Johns Hopkins University and placed a beaker of cat blood on his desk. “Can you please tell me when the blood clots” he asked? It never did. And that striking observation in 1916 turned out to be momentous in the history of science, opening the door to the discovery of heparin, the anticoagulant drug that dramatically altered the practice of medicine.

McLean was a medical student who had not exactly followed the beaten track. He had a tough childhood, losing his father when he was four years old and his home to the San Francisco fire when he was fifteen. During his last year of high school young McLean got his hands on a book about medical education and was smitten. But entry into medical school required an undergraduate degree which McLean decided to pursue at the University of California at Berkeley. It was here that he discovered a textbook on physiology written by William Howell, a professor of medicine at Johns Hopkins University in Baltimore. This was captivating stuff and McLean decided that Johns Hopkins Medical School was the place for him. But there was a problem. His application to Hopkins was denied.

Nevertheless, McLean decided to uproot himself and take a shot at talking his way in, and if that didn’t pan out, he’d work for a year and then try again. After managing to waggle an appointment with the Dean he was told that there was no recourse once an application had been denied. But then fate intervened. Word came the next day from the Dean about an unexpected vacancy. McLean would be admitted to medical school as long as he made up a missing requirement, a lab course in organic chemistry.

An overjoyed McLean then approached Dr. Howell and described how the professor’s text had triggered an interest in research in physiology which he believed would prepare him for a career in surgery. He now had a year to show that he could accomplish something significant by himself! The professor apparently liked the young man’s bravado and assigned him a project dealing with the coagulation of blood, his own area of interest. Howell had previously shown that a crude extract of brain tissue promoted blood clotting and suspected that the active ingredient was cephalin, a complex fatty substance belonging to a family of compounds known as phosphatides. McLean was to try to prepare cephalin in a pure form.

Working with macerated brain tissue that produced an insufferable odour turned out to be an unpleasant task. Worse, cephalin seemed to defy all attempts at isolation in a pure form. But McLean learned that German researchers had found heart and liver extracts with coagulant activity and figured that these might lead to an easier purification of cephalin. They didn’t. And then chance intervened once more. McLean decided to retest one of his phosphatide samples that had been stored for a while and discovered that not only had the coagulant activity been lost, it had been replaced by an anticoagulant effect!

Howell’s skepticism of the discovery prompted McLean to resort to the cat blood demonstration. But as his year of research was coming to an end, and medical school was calling, McLean regrettably had to abandon any further experiments. However, the idea of isolating an anticoagulant had been planted in Dr. Howell’s mind and within a couple of years he managed to isolate a water-soluble substance from the liver of a dog that in the laboratory had reproducible anticoagulant activity. “Heparin,” as he would name the extract from the Greek word for liver, had basically a carbohydrate structure, chemically very different from the fat-soluble cephalin.

Surgeons had long been plagued by the formation of blood clots as their scalpels damaged tissues. Also well known was the role of blood clots in heart attacks, pulmonary embolism and deep vein thrombosis. Any medication capable of preventing blood from clotting, in other words, an anticoagulant, would be most welcome! But the crude heparin preparations resulted in patients developing a variety of side effects, ranging from fever and chills to shock. Solving this problem appealed to Dr. Charles Best, who in 1929 had taken up a post as Professor of physiology at the University of Toronto.

Best, already famous for having assisted Frederick Banting in the discovery of insulin, headed a group that eventually managed to purify heparin. Important contributions were also made by a team of Swedish scientists under Erik Jorpes who had learned about heparin when he visited Best. Human trials began in 1935 and by the end of the decade heparin had entered clinical practice and remains an indispensable weapon in the medical armamentarium.

It took a while for the molecular structure of heparin to be determined, with many scientists playing important roles including McGill Professor Arthur Perlin who just happened to be my PhD research director. Heparin, as extracted from pork intestines or beef lung, is now known to be a family of carbohydrate polymers varying in molecular weight. Chemical processing methods have been developed to break down the long carbohydrate chains to yield “low molecular weight heparin” (Lovenox), which is widely used to treat deep vein thrombosis, prevent pulmonary embolism and reduce the risk of blood clot formation associated with a heart attack. No emergency room is without it

Although the term “wonder drug” is often recklessly bandied about, it isn’t too far off the mark when it refers to the substance without which cardiac surgery or dialysis would be impossible. Over the years there has been controversy about who should get credit for the discovery. Should it be McLean who first noted the anticoagulant effect, or Howell who managed to isolate the first sample of heparin? Most accounts lean towards Howell. Dr Hans Selye, known around the world as the father of stress research, suggested that in science credit should be attributed to the individual whose work has led directly to the development and application of the discovery. Since Jay McLean’s discovery led directly to Howell’s development of heparin, McLean should therefore get the credit. Although perhaps one could also make an argument for the gallant cat that donated the blood that stimulated the research leading to heparin.

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